Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease

University of Pennsylvania

Status and phase

Terminated

Phase 2

Conditions

Renal Insufficiency, Chronic

Treatments

Drug: ISMN

Dietary Supplement: Vitamin C

Study type

Interventional

Funder types

Other

Identifiers

NCT02791906

823665

Details and patient eligibility

About

Heart failure (HF) is an epidemic and is a major burden on the US healthcare system. The most common cardiovascular endpoint is HF. Thus, novel interventions to prevent HF in chronic kidney disease (CKD) are highly desirable. This study will assess: the variability in the response to isosorbide mononitrate (ISMN) therapy; the degree of change in central hemodynamics and cardiac endpoints through analysis of changes in left ventricle (LV) mass, diffuse myocardial fibrosis, and myocardial systolic and diastolic function.

Full description

This is a open label, parallel arm, randomized study of ISMN with or without vitamin C to improve exercise capacity and LV remodeling in CKD. Twenty subjects with CKD will be enrolled in this study and three different daily doses of sustained release isosorbide mononitrate (SR-ISMN) will be administered over time accompanied by a random administration of vitamin C in half of the subjects (500 mg three times daily). Before administration of SR-ISMN, baseline assessments will be performed. These include arterial tonometry, Doppler echocardiography, reflection magnitude measurements, a bicycle exercise test, activity monitoring, cardiac MRI, 24-hour blood pressure monitoring, and blood drawing. After these assessments, a dose of 30 mg of SR-ISMN will be administered daily (either with or without vitamin C) for the first week, 60 mg SR-ISMN for the second week, and 120 mg for the third week. After each week, blood pressure and central hemodynamics will be assessed. The third week visit also includes the bicycle exercise study and initiating the long term dose (60 or 120 mg) of SR-ISMN. In the long-term phase, blood pressure and hemodynamics are assessed at 12-weeks post initiation of the study medication(s). After 24 weeks we will perform the final assessment, which includes the same tests performed during the baseline assessment. Enrollment will take place at the Hospital of the University of Pennsylvania and the Penn Presbyterian Medical Center.

Enrollment

8 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Chronic kidney disease stage 3
Elevated left ventricular mass index or LV posterior wall thickness >1.4 cm documented in a clinically indicated echocardiographic or MRI examination within the previous 24 months or electrocardiographic LV hypertrophy
Stable medical therapy as defined by no addition, removal or change in dosage >100% of Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers for > 30 days
Current therapy with an ACE inhibitor, hydralazine or a statin, all of which have been shown to reduce nitrate tolerance

Exclusion criteria

A clinically- indicated stress test demonstrating significant myocardial ischemia within 1 year of enrollment, not followed by coronary revascularization
Rhythm other than sinus (i.e., atrial fibrillation)
Non-cardiac condition limiting life expectancy to <1 year
Current or anticipated future need for long acting organic nitrate therapy
Severe aortic or mitral valve disease
Hypertrophic cardiomyopathy
Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid)
Pericardial disease
Primary pulmonary arteriopathy
History of myocardial infarction, unstable angina, percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days, or requirement for either PTCA or CABG at the time of consent
Resting heart rate (HR) >100 bpm
A reduced LV ejection fraction (EF<50%)
Known severe liver disease (AST >3x normal, alkaline phosphatase or bilirubin >2x normal)
Allergy to ISMN
Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or tadalafil
Therapy with rosiglitazone
Current pregnancy or a positive urine pregnancy test; women who become pregnant during the study will be discontinued from the trial
Therapy with warfarin
History of kidney stones
History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
Systolic blood pressure <110 mmHg or diastolic blood pressure <40 mmHg;
Contraindications to a cardiac MRI: (a) Central nervous system aneurysm clips; (b) Implanted neural stimulators; (c) Implanted cardiac pacemaker or defibrillator; (d) Cochlear implant; (e) Ocular foreign body (e.g. metal shavings); (f) Other implanted medical devices: (e.g. drug infusion ports); (g) Insulin pump; (h) Metal shrapnel or bullet; (i) Claustrophobia; (j) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (k) Unwillingness of the patient to undergo a cardiac MRI.